4-O-Methylhonokiol is a potent CB2 receptor ligand (Ki = 50 nM), showing a unique inverse agonism and partial agonism via different pathways (cAMP and Ca2+) and potently inhibits osteoclastogenesis.[3] 4-O-Methylhonokiol further attenuates memory impairment in presenilin 2 mutant mice through reduction of oxidative damage and inactivation of astrocytes and the ERK pathway.[4] The different neuroprotective and anti-Alzheimer Disease effects reported in rodent models may be mediated via CB2 receptors, providing that the compound should be orally bioavailable to the brain.[5] It was shown that 4-O-methylhonokiol activates CB2 receptors and also inhibits the oxygenation of the major endocannabinoid 2-AG via COX-2 in a substrate-selective manner, thus leading to potential synergistic effects at CB receptors.[6] The same study also provided data that this natural product can readily pass the blood–brain barrier, using LC-MS/MS.